Journal of Advanced Research

Background: Major depressive disorder (MDD) is a severe mental illness associated with severe clinical consequences and substantial societal burden. It's characterized by immune-inflammatory dysregulation and immune sensitization. Objective: To determine whether in vitro ketamine attenuates phytohemagglutinin (PHA)/lipopolysaccharide (LPS)-induced immune sensitization in patients with MDD and healthy controls (HCs). Methods: Whole blood from 18 patients with MDD and 18 HCs was stimulated with PHA/LPS and exposed to ketamine (0.3 M, 0.6 M, and 6 M) for 72 hours. Cytokines, chemokines, growth factors, and composite immune profiles, including M1/M2 macrophages, T helper (Th)1/2/17, the immune-inflammatory response system (IRS), and compensatory immunoregulatory system (CIRS), were synthesized and determined. Results: Under PHA and LPS stimulation in vitro, the MDD group exhibited markedly elevated immune profiles, including M1, M2, Th1, Th2, Th17, IRS, CIRS, chemokines, and growth factors, consistent with immune sensitization. Significant group-by-treatment interactions were observed for Th1-Th2, M2, growth factors, IL-12(p70), M1, and chemokines. Ketamine produced minimal changes in HCs but broader suppression in MDD, particularly at the highest concentration, without normalizing the sensitized immune phenotype. Among the immune markers with no notable group-by-treatment interactions, ketamine exerted diagnosis-independent effects, decreasing MIP-1{beta}, IL-1&{beta}, Th1, TNF-{beta} IRS, IFN-{gamma}, and IL-2 compared to the control condition. Conclusions: Ketamine exhibited two distinct immunoregulatory patterns: selective, disease-dependent attenuation of sensitized immune pathways and broader, diagnosis-independent suppression of the stimulated immune response, predominantly at higher concentrations. However, these effects were insufficient to normalize the immune-sensitized phenotype of MDD.

Background: Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system marked by demyelination and neurodegeneration. Beyond physical symptoms, MS is often linked to clinically relevant sleep disturbances. The variability and unpredictability of symptoms and disease progression can also fuel fear of relapse (FoR), undermining well-being and potentially increasing morbidity through inflammatory processes. Understanding biopsychosocial risk factors, including childhood maltreatment (CM) and sleep, in relation to FoR remains an important gap in MS management and research. Methods: Data from N = 48 participants were collected via an online survey. We used the Pittsburgh Sleep Quality Index (PSQI), the Fear-of-Relapse Scale (FoR), and the Childhood Trauma Questionnaire (CTQ) to assess the variables of interest. In addition, time points of exposure to different CM subtypes were assessed. Linear regression analyses were conducted to examine associations within the proposed negative triad. Results: A significant negative association between overall sleep quality and FoR was observed. In the total cohort, the interaction between CM and sleep was not a significant predictor of FoR. However, exploratory analysis revealed a significant interaction between CM and sleep among male participants, whereas the same interaction was not significant among female participants. Conclusion: A history of CM and impaired sleep quality introduce new stressors in managing one's own illness that have received little attention to date. However, the present study found that these factors were at least partly influential on the FoR. The results underscore the translational need for additional support services to enhance prevention and personalized care.

Aim: The Patient Safety Screener-3 (PSS-3) is a brief suicide-risk screening tool. Item 1 of this scale assesses depressive mood but is not included in the total score. We examined the association of item 1 with depressive symptom severity and characterized the suicide-related risk captured by PSS-3 total positivity. Methods: We conducted a nationwide cross-sectional survey among resident physicians in Japan. Associations between PSS-3 item 1 endorsement and Patient Health Questionnaire-9 (PHQ-9) scores were evaluated using the Wilcoxon rank-sum test. Diagnostic performance of item 1 was evaluated using PHQ-9 positivity ([&ge;]10) as reference standard. We also compared Short-form Scale for Suicide Ideation (SIS-6) scores according to PSS-3 total positivity and PHQ-9 item 9 positivity. Results: A total of 1,844 participants were included. PSS-3 item 1 was endorsed by 443 physicians (24.0%), and 47 (2.5%) met the criteria for PSS-3 total positivity. Item 1 showed 79.3% sensitivity and 79.5% specificity for PHQ-9 positivity. SIS-6 scores were higher in the PSS-3 total-positive group than in the total-negative group (median [IQR], 6 [5-9] vs 0 [0-1]; p<0.001). The SIS-6 showed a higher area under the receiver operating characteristic curve (AUC) and Youden index using PSS-3 total positivity (AUC, 0.961; optimal cutoff, 3) than PHQ-9 item 9 positivity (AUC, 0.907; optimal cutoff, 2). Discussion: PSS-3 may support brief, simultaneous screening for depressive symptoms and suicide-related risk. Compared with PHQ-9 item 9, PSS-3 may capture a more severe spectrum of suicide-related risk. PSS-3 may facilitate identification of individuals requiring further mental health assessment.

Mood fluctuations in major depressive disorder are difficult to anticipate. The biological neural rhythms that organize mood dynamics over days to weeks remain unknown. In individuals implanted with a chronic neural sensing and stimulation device for treatment-resistant depression, we collected years-long intracranial neural recordings alongside daily mood ratings. Both mood and limbic neural activity fluctuated cyclically with multiday (multidien) periodicities of 2-34 days. An individual's daily phase position within mood cycles tracked depression severity, distinguishing whether symptoms were rising, peaking, or resolving. Neural rhythms led mood cycles and forecast an individual's mood trajectory up to 30 days in advance, outperforming models based on raw neural activity. Electrical stimulation reshaped these rhythms, shifting individuals away from the peak-depression phase of their multidien cycle. Our results identify multidien rhythms as an organizing principle of mood in depression and a forecastable, modifiable target for chronotherapeutic neuromodulation.

Abstract Imaging-based spatially resolved transcriptomics (imSRT) technologies provide high-throughput molecular-resolution spatial characterization of genes within cells. Conventional analysis methods to identify cell-types and states in imSRT data rely on gene count matrices derived from tallying the number of mRNA molecules detected for each gene per segmented cell, thereby overlooking subcellular heterogeneity that can be useful in defining cell states. To take advantage of the molecular-resolution information in imSRT data and potentially identify cell-states based on subcellular heterogeneity, we developed STARIT (Spatial Transcriptomics As Rasterized Image Tensors). STARIT converts transcripts within segmented cells in imSRT data into an image-based tensor representation that can be combined with deep learning computer vision models for downstream analysis. Using simulated and real imSRT data, we demonstrate that STARIT distinguishes transcriptionally distinct cell-types and further separates cell states based on subcellular transcript localization, which conventional gene count analysis fails to capture. By providing a standardized framework to encode subcellular molecular information in imSRT data, STARIT will enable deeper insights into subcellular heterogeneity and enhance the identification and characterization of cell-types and states that are overlooked by gene count representations.

Hepatocellular carcinoma (HCC) is particularly aggressive and difficult to treat. Due to the lack of early clinical diagnosis and the unsatisfactory clinical treatment effect, it is particularly important to identify novel markers that can predict tumor behavior in HCC. biogenesis of ribosomes BRX1 (BRIX1) is abundant in various tissues of the human body. However, the regulatory mechanisms and its role in various tissues are not fully understood. Here, we analyzed the expression pattern of BRIX1 in HCC from public gene expression databases and tissue samples from clinical HCC. We confirmed that BRIX1 was upregulated in both HCC cell lines and HCC paraffin section samples. BRIX1 depletion significantly dicreased the capacity of cells to grow and migrate in vitro, and knockdown BRIX1 suppressed tumor growth in xenograft tumor model. Mechanistically, BRIX1 depletion suppressed the MAPK/ERK pathway, as reflected by reduced phosphorylated ERK (p-ERK) levels. In summary, we provide a rational clue for the further investigation of BRIX1 as an invaluable biological marker for diagnosing and predicting prognosis of patients with HCC.

Post-COVID-19 syndrome (PCS) is characterized by fatigue, neurological impairment and systemic symptoms. This heterogeneity of symptoms hinders biomarker development. Here, we profiled extracellular-vesicle (EV) surface markers in plasma and CSF from 61 participants with PCS (COVIDpost), 80 recovered controls (COVIDreco), and 10 participants with non-SARS-CoV-2 post-viral syndromes. EVs were analysed by bead-based multiplex flow cytometry using tetraspanin-directed (TSPN) and phosphatidylserine-directed lactadherin (PS) detection. Amongst 37 targets covering tetraspanins and vasculature-, immunity- and stemness-associated markers, none met a 1% false-discovery-rate threshold. However, L1-regularized logistic regression under fully nested 5x5 cross-validation identified a distributed plasma EV profile, with mean out-of-fold areas under the receiver operating characteristic curve (AUCs) of 0.788 (95% CI 0.715 - 0.852) for TSPN and 0.716 (95% CI 0.636 - 0.792) for PS detection. Across the pooled COVIDpost and COVIDreco population, EV classification scores covaried with clinical group differences, but did not track clinical severity within either cohort. These PCS-EV classification scores decreased at one-year follow-up in COVIDpost participants. Our findings identify an internally cross-validated multivariable EV surface profile associated with COVIDpost versus COVIDreco status and support independent validation and exploration of EV-based biomarkers in post-viral fatigue syndromes.

The lack of effective anti-JEV therapy possesses significant challenge to control JEV. {beta}-catenin, a key mediator of Wnt signaling pathway regulates different viral replication and host immune responses. However, its role in JEV infection remains to be elucidated. Thus, the current study focused on evaluating iCRT-14, a specific {beta}-catenin inhibitor, against JEV. Treatment with iCRT-14 following JEV infection resulted efficient reduction in viral progeny release, viral RNA and protein levels in Huh7 and HEK293T cells. Further, active and total {beta}-catenin, Cyclin D-1 and GSK3-{beta}, the other key pathway players were also modulated in infected and inhibitor treated cells. Moreover, iCRT-14 showed an IC of 4.56 in Huh7 cell and maximal inhibition at the early stages of the JEV life cycle. Interestingly, the overexpression of {beta}-catenin in both the cells and siRNA-mediated {beta}-catenin knockdown (in Huh7 cells) significantly abrogated JEV replication, as evidenced by decreased viral titers, viral protein expression, and viral as well as total RNA levels. Moreover, the reduction in extracellular (84%) and intracellular (60%) viral titers following iCRT-14 treatment highlights its role in impairing JEV infection. Further, in silico molecular docking and co-immunoprecipitation studies demonstrated interactions between {beta}-catenin and the JEV NS5 and E proteins. Collectively, these findings suggest that optimum level of {beta}-catenin is required for efficient JEV infection, highlighting its potential as a target for designing host-directed control strategies to regulate viral infection.

INTRODUCTION: Biomarkers for monitoring disease activity and treatment response in peripheral neuropathies remain limited. Big tau, a high-molecular-weight isoform of tau, is predominantly expressed in the peripheral nervous system (PNS). We investigated serum levels of big tau, brain-derived tau (BD-tau), and neurofilament light chain (NfL) in peripheral neuropathies, multiple sclerosis (MS), Alzheimer disease (AD), and healthy controls (HC). METHODS: Ultra-sensitive blood-based assays run on an HD-X Single Molecule Array analyser (Quanterix) were used to measure big tau and BD-tau in serum from patients with Guillain-Barr&eacute syndrome (GBS, n=81), Miller Fisher syndrome (MFS, n=20), Charcot-Marie-Tooth disease (CMT, n=102), chronic inflammatory demyelinating polyneuropathy (CIDP, n=43), MS (n=159), AD (n=20), and HC (n=41). NfL was measured in patients with neuropathies using an SR-X Single Molecule Array analyser (Quanterix). RESULTS: Serum big tau levels were higher in GBS than in AD (11.4 vs 2.4 pg/mL, p<0.0001) and MS (11.4 vs 9.0 pg/mL, p=0.01), and similar to CIDP and CMT. Contrarily, serum BD-tau levels in GBS were higher than in CIDP (3.0 vs 2.3 pg/mL, p=0.006) and MS (3.0 vs 1.7 pg/mL, p<0.0001), but similar to CMT, and lower than in AD (3.0 vs 9.8 pg/mL, p<0.0001). Serum NfL levels were higher in GBS than in CIDP (32.5 vs 13.0 pg/mL, p=0.0002), CMT (32.5 vs 12.3 pg/mL, p<0.0001), and HC (32.5 vs 7.6 pg/mL, p<0.0001). Compared with GBS, MFS patients showed higher BD-tau (12.7 vs 3.0 pg/mL, p=0.003), lower big tau (5.4 vs 11.4 pg/mL, p=0.002), and higher NfL levels, although the latter did not reach statistical significance (118.3 vs 32.5 pg/mL, p=0.16). The NfL/big tau ratio was significantly higher in MFS than in GBS, CIDP, and CMT. In GBS, BD-tau correlated with early clinical severity (MRC at 1 week; I-RODS at 4 weeks; maximum GBS-DS and GBS-DS at 4 weeks), whereas neither tau biomarker showed long-term clinical correlations. Higher BD-tau and big tau levels were associated with the need for mechanical ventilation (BD-tau: 8.6 vs 2.9 pg/mL, p=0.019; big tau: 19.7 vs 10.7 pg/mL, p=0.007), while higher BD-tau levels were associated with mortality (10.9 vs 2.9 pg/mL, p=0.003). CONCLUSIONS: Higher big tau levels in peripheral neuropathies than in CNS diseases support its role as a PNS-specific biomarker. In MFS, increased serum BD-tau, reduced big tau, and an elevated NfL/big tau ratio suggest CNS involvement with relative preservation of the PNS.

Background The prevalence and pattern of secondary causes of first-onset psychosis (FEP) in Asian populations are understudied. Our objectives are to investigate the prevalence and pattern of secondary causes of FEP presenting in an acute medical setting in a metropolitan, Chinese-predominant population, and to investigate the prevalence and pattern of undiagnosed conditions presenting as psychosis. Method This is a retrospective observational study. We reviewed medical records of patients referred to the consultation psychiatry team at a tertiary acute teaching hospital in Hong Kong from January 2015 to Apr 2025. The inclusion criteria of the study are 1) age 18-64 at the time of the assessment, and 2) FEP confirmed by the consultation liaison team. Patients diagnosed with delirium were excluded. Result Among the 384 patients included in the study (mean age = 40.0 {+/-}13.7 years, 69% female), secondary causes of psychosis were found in 9.6% (n=37) of the cohort. Substance use is the most common secondary cause found (n=11, 2.9% of all FEPs) overall. Among those with secondary psychoses, patients' underlying conditions were revealed only by the workup in relation to the FEP in 16 of them, of which definitive or probable autoimmune encephalitis (n=5) and early-onset dementia (n=4) were the most common conditions uncovered. Conclusion The prevalence of secondary psychoses in our FEP cohort is lower than published international figures. Clinicians need to be aware of the suspicious clinical features suggestive of autoimmune encephalitis and early-onset dementia in FEP patients with otherwise unremarkable past history and toxicology test.

Major depressive disorder (MDD) is strongly associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, systemic inflammation, and gut microbiota dysbiosis. Although selective serotonin reuptake inhibitors such as escitalopram are standard treatments, their efficacy is often constrained by partial response and gastrointestinal adverse effects. In this 12-week, randomized, double-blind, placebo-controlled trial, we evaluated the clinical efficacy and microecological mechanisms of adjunctive Lactiplantibacillus plantarum PS128 (PS128; 6*1010CFU/day) in MDD patients on stable escitalopram therapy. Adjunctive PS128 significantly enhanced clinical response compared to placebo, yielding substantial reductions in HAMD-17 and MADRS, alongside a higher remission rate. 16S rRNA sequencing and PICRUSt2 profiling revealed that PS128 enriched key short-chain fatty acid producers (Faecalibacterium, Coprococcus), counteracting the Klebsiella expansion seen in placebo. Functionally, PS128 up-regulated neuroprotective cofactor, B vitamins, biosynthesis and down-regulated the neurotoxic kynurenine pathway. Network analysis demonstrated that PS128 maintained a resilient, integrated microbial co-occurrence topology, whereas the placebo network showed structural segregation. This stabilized ecosystem attenuated peripheral inflammatory signaling and normalized salivary cortisol levels. Overall, adjunctive PS128 augments escitalopram efficacy by enhancing gut network stability, supporting cellular energetics, and modulating neuroendocrine activity, offering a promising multimodal strategy for MDD.

Background: The primary neuroanatomical site of Huntington-s disease (HD) pathology resides in the striatum and its atrophy identifies important disease progression from HD-ISS Stage 0 to Stage 1. Immune-associated proteins may capture variation in HD that is incompletely represented by markers of neuroaxonal injury. Objectives: To determine whether cerebrospinal-fluid myeloperoxidase contributes information about striatal volume loss beyond genetic disease burden and neurofilament light. Methods: Cross-sectional data from 88 persons with HD were analyzed. Cerebrospinal-fluid myeloperoxidase and neurofilament light were measured with a nucleic acid-linked immunosandwich assay. Normalized putamen volume was derived from structural magnetic resonance imaging. Linear regression adjusted for genetic disease burden and sex. Results: Higher neurofilament light was associated with smaller normalized putamen volume (standardized {beta} = -0.322, (P=.0066)). Higher myeloperoxidase was associated with larger normalized putamen volume after adjustment for genetic disease burden, sex, and neurofilament light (standardized {beta} = 0.183, (P=.0386)). Adding myeloperoxidase increased explained variance in striatal loss. Conclusions: Cerebrospinal fluid myeloperoxidase contributed modest incremental information about striatal volume in this cross-sectional sample. Independent longitudinal studies are needed to determine its biological source, temporal behavior, and potential biomarker value. Findings advance efforts to characterize multicomponent biological markers of HD.

Background: Primary malignant cardiac tumors (PMCTs) are rare and histologically heterogeneous. Objective: To compare demographics, specific ICD-O-3 morphologies, first-course treatment patterns, annual registered case counts, and unadjusted overall survival between soft-tissue and hematologic PMCTs. Methods: We identified 730 PMCT cases diagnosed from 2000 to 2021 in SEER 18 (ICD-O-3 topography C38.0). Histologic lineage was assigned from ICD-O-3 morphology. Comparative analyses included soft-tissue (n=458) and hematologic (n=212) tumors. First-course variables were primary-site surgery, chemotherapy (yes versus no/unknown), and radiotherapy (radiation versus none/unknown). Groups were compared with chi-square tests. Overall survival was estimated with Kaplan-Meier methods; follow-up was truncated at 120 months. Results: Soft-tissue PMCTs occurred predominantly at ages 45-64 years (67.9%), whereas hematologic PMCTs occurred predominantly at age [&ge;]65 years (63.2%; p<0.001). Men comprised 59.9% of hematologic and 49.3% of soft-tissue cases (p=0.014). The leading soft-tissue morphology was hemangiosarcoma/angiosarcoma (ICD-O-3 9120/3; 201/458, 43.9%); synovial sarcoma accounted for 20/458 cases (4.4%). Diffuse large B-cell lymphoma, NOS, accounted for 131/212 hematologic tumors (61.8%). Any primary-site surgery was recorded in 66.6% of soft-tissue versus 15.6% of hematologic cases (p<0.001). Chemotherapy was recorded in 67.5% versus 51.1% (p<0.001), and radiotherapy in 9.0% versus 20.5% (p<0.001). In exploratory Kaplan-Meier analyses, hematologic patients with recorded chemotherapy had higher unadjusted 120-month overall survival than those without recorded chemotherapy (42.0% versus 12.2%; log-rank p=7.5x10-). Radiation-associated survival differences were not statistically significant in either lineage. Conclusions: Soft-tissue and hematologic PMCTs have distinct age distributions, named histologies, and first-course treatment patterns in SEER. These findings describe registry coding and do not establish treatment effectiveness or population incidence.

Background: The Boston Criteria v2.0 represent the gold standard for diagnosing Cerebral Amyloid Angiopathy (CAA), but their application is currently precluded in mixed small vessel disease (SVD), where deep and lobar hemorrhages coexist. The aims of this study are: (i) to determine which cerebrospinal fluid (CSF) biomarker (A{beta}42, A{beta}40, A{beta}42/40 ratio) is the best candidate to support the CAA diagnosis; (ii) to define a data-driven cut-off, and (iii) to explore if a biomarker-integrated classification significantly improves the phenotypical concordance with the suspected predominant SVD (CAA vs. arteriosclerosis). Methods: We analyzed data from a retrospective multicenter cohort of patients with suspected CAA, defined as probable CAA (Boston criteria v2.0) but allowing deep hemorrhagic lesions, and with available CSF biomarkers. We visually quantified MRI-visible SVD markers (e.g., cerebral microbleeds [CMB], cortical superficial siderosis [cSS], lacunes) and their association with MRI-visible SVD features. We employed a Gaussian Mixture Model (GMM) to identify a data-driven threshold for amyloid positivity (A+). Then, we compared the prevalence of MRI-visible manifestations of SVD between subgroups applying different frameworks, namely the current MRI-based classification (probable CAA vs. mixed SVD) and a CSF biomarker-integrated classification (A+ vs. A-). Results: We enrolled 121 patients (age: 72 [66-77] years; 60% probable CAA, 40% mixed SVD with suspected CAA). The CSF A{beta}42/40 ratio showed a bimodal distribution and consistent associations with all CAA-specific radiological features. The CSF biomarker-integrated reclassification, particularly using the GMM cut-off, significantly improved the distinction between subgroups regarding CAA- and arteriosclerosis-related MRI features (e.g., cSS presence: probable CAA vs. mixed SVD: aOR=2.84 [95%CI 1.27-6.39], p=0.011; A+ vs. A-: aOR=12.68 [95%CI 4.31-37.32], p<0.001; deep lacunes presence: probable CAA vs. mixed SVD: aOR=0.20 [95%CI 0.08-0.50], p<0.001; A+ vs. A-: aOR=0.04 [95%CI 0.01-0.11], p<0.001). Notably, patients classified as A+ never demonstrated more than four deep CMBs. Discussion: A CSF biomarker-integrated classification may improve the classification of CAA compared with the current MRI-based framework. These findings are cohort-specific and would benefit from further validation, especially with a neuropathological reference. Still, these results support a future transition toward an integrated biological-radiological framework, which may refine in vivo CAA diagnosis, particularly in mixed SVD.

Ulcerative colitis (UC) and radiation enteropathy involve intestinal epithelial injury, barrier dysfunction, and inflammation, but effective treatments remain limited. This study evaluated MXC-017, a novel vimentin-targeting urea compound, in mouse models of dextran sulfate sodium (DSS)-induced colitis and radiation-induced enteropathy. Acute colitis was induced in C57BL/6 mice using 3.5% DSS for seven days, followed by regular water for seven days. Radiation enteropathy was induced by 13 Gy total abdominal irradiation. Mice received MXC-017 (150 mg/kg) or vehicle. Disease activity, intestinal permeability, inflammatory and epithelial markers, and histopathology were assessed. MXC-017's effects on cancer stem cell frequency, sphere formation, and migration were also examined in PC-3 and DU-145 prostate cancer cells. MXC-017 reduced DSS-induced colitis severity, accelerated weight recovery, lowered disease activity, partially preserved colon length, and restored barrier function. It also reduced proinflammatory cytokines, macrophage infiltration, epithelial injury, and goblet cell loss while preserving epithelial proliferation and markers of intestinal stem cell function and tight-junction integrity. Following irradiation, MXC-017 improved weight recovery, reduced intestinal permeability, preserved epithelial architecture, and partially mitigated villus shortening. Importantly, MXC-017 did not protect prostate cancer stem cells from radiation. Instead, it reduced stem cell frequency, sphere-forming capacity, and cancer cell migration. These findings support vimentin targeting with MXC-017 as a potential treatment for UC and radiation-induced intestinal toxicity and as an adjunct to radiotherapy for pelvic and abdominal malignancies.

Background: Previous trauma research includes many limitations, such as the scarcity of pretraumatic health measurements and assessment of traumatic experiences with a broad scope across the lifespan. To respond to these gaps, we aimed to develop a new, prospective, population-based trauma dataset from childhood to middle age. Methods: We used the Young Finns Study that is a population-based, multi-generational, prospective study (n = 3596 for the main generation). It has started in 1980 (baseline assessment) and includes follow-ups in 1983, 1986, 1989, 1992, 1997, 2001, 2007, 2011/2012, and 2018-2020. From the 38-year follow-up and ten measurement points of the YFS, we collected all relevant trauma variables, including both free-format and structured questions that both the participants and their parents responded to. By a data-driven case-to-case analysis, we developed a scale to numerically capture variation in the quality of the experiences. Results: Our final dataset captured a total of 7769 traumatic experiences. We also developed the Traumatic Experience Severity Scale (TESS), including six subscales such as shamefulness, rarity, danger to life or health, effects on everyday life, human-made physical threat, and whether the target person was within or outside one's household. We also preprocessed the dataset to be later easily interleaved with other psychological, cardiovascular, and epigenetic variables of the YFS. Conclusions: We believe this new trauma dataset with thousands of experiences across the lifespan provides new opportunities to multidisciplinary, lifelong trauma research.

Objective White smoke inhalation injury (WSI) causes severe acute lung damage with no specific therapy currently available. Sphingolipid metabolism is implicated in pulmonary inflammation, but its transcriptional regulatory landscape in WSI remains unexplored. This study aimed to identify key sphingolipid metabolism related genes and evaluate their regulatory roles and therapeutic potential in WSI. Methods We established a rat model of WSI and performed integrated bulk RNA sequencing, weighted gene coexpression network analysis (WGCNA), and single-cell RNA sequencing (scRNAseq) to screen for differentially expressed sphingolipid metabolism-related genes (DESRGs). Protein-protein interaction (PPI) network with four centrality algorithms was used to prioritize hub genes. In silico gene knockout and molecular docking were conducted to assess regulatory functions and identify potential drug candidates. Results We identified 22 DESRGs that were predominantly enriched in DNA replication and cell cycle pathways rather than canonical sphingolipid metabolic processes. PPI consensus prioritized three hub genes--Top2a, Ttk, and Ccna2--with Top2a exhibiting the highest expression in epithelial cells and significant downregulation after smoke exposure. ScRNAseq revealed immune cell infiltration and epithelial differentiation trajectories. Virtual knockout showed that Top2a depletion affected the largest transcriptomic fraction (~0.4%) and was enriched in lysosome biogenesis, innate immunity, phagocytosis, and lipid catabolism. Molecular docking identified thalidomide as a high affinity ligand for Top2a (Vina score: -8.5 kcal/mol). Conclusion Our multiomics integrative framework identifies Top2a as a central regulatory hub linking sphingolipid associated inflammation to epithelial responses in WSI, and nominates thalidomide as a potential drug repurposing candidate. These findings provide prioritized targets for future translational investigation.

Suicidal behavior results from complex behavioral and biological changes. Previous cross-sectional studies indicate that proinflammatory immunobiological factors are often increased in close temporal proximity to a suicide attempt. Suicidal individuals may also exhibit a biological trait vulnerability to stress and inflammation, due to persistent epigenetic modifications. We enrolled 130 individuals with major depressive disorder (MDD), 83 with suicidal behavior at intake, and followed them for 12 months with up to eight clinical assessments. Quantification of plasma inflammatory markers and metabolites was performed by high-sensitivity electrochemiluminescence and Ultra High-Performance-Liquid-Mass Spectrometry (UPLC-MS), respectively. Epigenetic changes were identified using Illumina EPIC arrays. We identified 15 genes with altered DNA-methylation associated with suicidal behavior and attempts at baseline. Childhood trauma predicted lifetime suicide attempts and was associated with altered methylation of seven genes. Increased neutrophils and lower plasma serotonin at baseline predicted future suicide attempts over the following year (neutrophil estimate = 0.42, P = 0.016; serotonin OR = 0.58, 95% CI: 0.39-1.13). Utilizing biomarkers from baseline and epigenetic data from the genes with highest predictive values (STBD1 ,PRDM8, and TRIM15), we achieved an area under the curve (AUC) of 0.84 for suicide attempts over the year. Suicidal behavior in MDD was associated with specific epigenetic signatures. Several of the identified genes, such as MAD1L1, have been implicated in psychiatric disease, suicidal behavior and the immune response. These findings support the usefulness of epigenetic and immunometabolic blood markers for identifying suicidal individuals in clinical settings, potentially enhancing preventative efforts.

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

Neurodegenerative diseases are increasingly associated with vascular dysfunction beyond progressive neuronal degeneration, yet how vascular pathology contributes to disease progression remains poorly understood, largely due to the lack of a neurodegenerative disease model capable of capturing neuronal pathology alongside associated vascular dysfunction. Here, we developed a microengineered 3D vascularized brain tissue model that integrates neurospheroids with a self-assembled, perfusable vascular network to recapitulate key features of the neurovascular interface. Using this model, we investigated the vascular contribution to Parkinson's disease pathology by introducing -synuclein preformed fibrils into the engineered vasculature. Intravascular -syn fibril exposure induced endothelial barrier disruption, vascular leakage, inflammation, and vascular regression. Notably, this vascular insult was accompanied by intraneuronal -synuclein aggregation within neurospheroids, suggesting that vascular dysfunction may facilitate the exposure of neural tissue to pathogenic -synuclein. Our neurodegenerative disease modeling approach establishes a versatile and tractable platform for investigating vascular contributions to neurodegenerative disease progression.